New clinical research strategies in thoracic oncology: clinical trial design, adaptive, basket and umbrella trials, new end-points and new evaluations of response

Abstract

In the genomics era, our main goal should be to identify large and meaningful differences in small, molecularly selected groups of patients. Classical phase I, II and III models for drug development require large resources, limiting the number of experimental agents that can be tested and making the evaluation of targeted agents inefficient. There is an urgent need to streamline the development of new compounds, with the aim of identifying "trials designed to learn", which could lead to subsequent "trials designed to conclude". Basket trials are often viewed as parallel phase II trials within the same entity, designed on the basis of a common denominator, which can be a molecular alteration(s). Most basket trials are histology-independent and aberration-specific clinical trials. Umbrella trials are built on a centrally performed molecular portrait and molecularly selected cohorts with matched drugs, and can include patients' randomisation and strategy validation. Beyond new designs, new end-points and new evaluation techniques are also warranted to finally achieve methodology and clinical improvements, in particular within immunotherapy trials.

Figure 1.

a) Schematic example of a basket trial. These trials are often viewed as parallel, phase II trials for one drug, but within the same legal entity on the basis of a common denominator that can be molecular alteration(s). Most basket trials are histology-independent and aberration-specific clinical trials if a predictive marker is used. These trials are usually tested locally and often fall into the “trial to learn” category. b) Schematic illustration of the Vemurafenib basket trial [10]. NSCLC: nonsmall cell lung cancer. Images courtesy of Gustave Roussy Cancer Campus Grand Paris, Villejuif, France.

Figure 2.

a) Schematic example of an umbrella trial. These trials embrace centralised analysis to define the molecular portrait and molecularly selected cohorts with matched drugs [7]. These trials may fall into the “trial to conclude” category. b) Schematic illustration of the SAFIR02_Lung trial (Intergroup Trial UNICANCER UC 0105-1305/IFCT 1301). This is an open-label, multicentric, randomised, phase II trial [11]. NSCLC: nonsmall cell lung cancer; EGFR: epidermal growth factor receptor; ALK: anaplastic lymphoma kinase; CGH: comparative genomic hybridisation. Images courtesy of Gustave Roussy Cancer Campus Grand Paris, Villejuif, France.